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Purpose of Review This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have yielded novel insights into potential mechanisms of demyelination.

Recent Findings The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration. Active MS lesions show a profound pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups. Recent pathologic studies have suggested that the subarachnoid space and cortex may be initial sites and targets of the MS disease process, that inflammatory cortical demyelination is present early in MS, and that meningeal inflammation may drive cortical and white matter injury in some MS patients.

Summary MS is heterogeneous with respect to clinical, genetic, radiographic, and pathologic features; surrogate MRI, clinical, genetic, serologic, and/or CSF markers for each of the four immunopatterns need to be developed in order to recognize them in the general nonbiopsied MS population. Inflammatory cortical demyelination is an important early event in the pathogenesis of MS and may be driven by meningeal inflammation. These observations stress the importance of developing imaging techniques able to capture early inflammatory cortical demyelination in order to better understand the disease pathogenesis and to determine the impact of potential disease-modifying therapies on the cortex.

Relationship Disclosure: Dr Popescu has served as a speaker for Teva Canada Innovation and receives research support from the Canada Research Chairs program and the Saskatchewan Health Research Foundation. Dr Pirko serves as the clinical editor of Nanomedicine: Nanotechnology, Biology and Medicine and receives research support from the NIH. Dr Lucchinetti holds a patent for aquaporin-4–associated antibodies for the diagnosis of neuromyelitis optica; receives royalties from Elsevier for the publication of Blue Books of Neurology: Multiple Sclerosis; and receives research support from Guthy-Jackson Charitable Foundation, the National Multiple Sclerosis Society, and the NIH.

Unlabeled Use of Products/Investigational Use Disclosure: Drs Popescu, Pirko, and Lucchinetti report no disclosures.